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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or the PARP inhibitor AZD2461 (iP) in CRPC cell lines 22Rv1 and PC3. DHA enhanced the cytotoxic effect of iP in both cell lines and of ENZ in 22Rv1 cells. In PC3 cells, DHA-mediated potentiation of iP cytotoxicity was associated with downregulation of the AKT pathway, reduced expression of ER\u03b1 and the lipid sensors PPAR\u03b3 and LXR\u03b2, and a shift in programmed cell death toward necroptosis. In 22Rv1 cells, the additive effects of DHA with ENZ or iP were independent of PI3K\/pAKT and AR-FL\/AR-V7 modulation but were associated with regulation of LXR\u03b2, PPAR\u03b3, and TNFR1, along with activation of apoptosis. Wound-healing assays showed that DHA blocked the anti-migratory effects of ENZ and iP in 22Rv1 cells and did not alter iP effects in PC3 cells, indicating epithelial\u2013mesenchymal transition heterogeneity. Overall, DHA potentiates the cytotoxic effects of iP in both models and of ENZ in 22Rv1 cells via differential modulation of cell death in a molecular context-dependent manner.<\/jats:p>","DOI":"10.3390\/ijms27188037","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:01:56Z","timestamp":1788966116000},"page":"8037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Docosahexaenoic Acid Enhances the Cytotoxic Effects of Enzalutamide and the PARP Inhibitor in Castration-Resistant Prostate Cancer Cell Lines"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6445-7446","authenticated-orcid":false,"given":"Alana Della Torre","family":"da Silva","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Laurielle do Prado","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Daniele Lisboa","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Histology and Embryology, Institute of Biomedical Sciences, Federal University of Uberl\u00e2ndia (UFU), Uberl\u00e2ndia 38405-318, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6584-6566","authenticated-orcid":false,"given":"Guilherme Henrique","family":"Tamarindo","sequence":"additional","affiliation":[{"name":"Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3622-460X","authenticated-orcid":false,"given":"Rejane Maira","family":"G\u00f3es","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","first-page":"e46639","article-title":"The Impact of Modern Dietary Practices on Cancer Risk and Progression: A Systematic Review","volume":"15","author":"Nagy","year":"2023","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Li, C., Jing, Z., Guo, Q., Zheng, Z., Zhao, X., Yuan, W., Xi, Y., and Wang, J. 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